Conventional drug delivery technology, which in the past has concentrated on improvements in mechanical devices such as implants or pumps to achieve more sustained release of drugs, is now advancing on a microscopic and even molecular level. Recombinant technology has produced a variety of new potential therapeutics in the form of peptides and proteins and these successes have spurred the search for newer and more appropriate delivery and targeting methods and vehicles.
Microencapsulation of drugs within biodegradable polymers and liposomes has achieved successes in improving the pharmacodynamics of a variety of drugs such as antibiotics and chemotherapeutic agents. For example, unilamellar vesicles are currently used as drug delivery vehicles for a number of compounds where slow, sustained release or targeted release to specific sites in the body are desired. The drug to be released is contained within the aqueous interior of the vesicle and release is achieved by slow permeation through the vesicle bilayer. A variety of modifications of the unilamellar vesicle membrane have been attempted, including polymerizing or crosslinking the molecules in the bilayer to enhance stability and reduce permeation rates, and incorporating polymers into the bilayer to reduce clearance by macrophages in the bloodstream.
One example of such a vesicle structure is known as Depofoam. Depofoam is a multivesicular particle that is created by multiple emulsification steps. A defined lipid composition is dissolved in a volatile solvent. The dispersed lipids in solvent are vigorously mixed with water to form a first emulsion, designated a solvent continuous emulsion.
This first emulsion is then added to a second water/solvent emulsion and emulsified to form a water in solvent in water double emulsion. The solvent is removed from the mixture resulting in discrete foam-like spherical structures consisting of bilayer separated water compartments. The minimum size of these structures is about 5-10 microns. Depofoam does not include a distinct bilayer structure that encapsulates the multivesicular particles, i.e., there are no individual, distinct interior vesicles. Therefore, the interior compartment must share bilayer walls.
Liposomes are sealed, usually spherical, either unilamellar or multilamellar vesicles which are capable of encapsulating a variety of drugs. Liposomes are the most widely studied vesicles to date and they can be formulated with a variety of lipid types and compositions that can alter their stability, pharmacokinetics and biodistribution. A major disadvantage of both multilamellar and unilamellar liposomes as delivery systems is their size, which prevents them from crossing most normal membrane barriers and limits their administration to the intravenous route. In addition, their tissue selectivity is limited to the reticuloendothelial cells, which recognize them as foreign microparticulates and then concentrates the liposomes in tissues such as the liver and spleen.
Polymers have also been used as drug delivery systems. They generally release drugs by (1) polymeric degradation or chemical cleavage of the drug from the polymer, (2) swelling of the polymer to release drugs trapped within the polymeric chains, (3) osmotic pressure effects, which create pores that release a drug which is dispersed within a polymeric network, and/or (4) simple diffusion of the drug from within the polymeric matrix to the surrounding medium.
With the success and drawbacks of these microencapsulation vehicles, today the challenge is to produce better and more efficient microencapsulation vehicles to enhance drug delivery. The present invention is directed to meeting that challenge.